Optimization and synthesis of an 18 F‐labeled dopamine D 3 receptor ligand using [ 18 F]fluorophenylazocarboxylic tert ‐butylester

There is still no efficient fluorine‐18‐labeled dopamine D 3 subtype selective receptor ligand for studies with positron emission tomography. We aim at improving the D 3 selectivity and hydrophilicity of a candidate ligand by changing the substitution pattern to a 2,3‐dichlorophenylpiperazine and hydroxylation of the butyl chain. The compound [ 18 F]3 exhibited D 3 affinity of K i  = 3.6 nM, increased subtype selectivity (K i (D 2 /D 3 ) = 60), and low affinity to 5‐HT 1A and α 1 receptors (K i (5‐HT 1A /D 3 )  = 34; K i (α 1 /D 3 ) = 100). The two‐step radiosynthesis was optimized for analog [ 18 F]4 by reducing the necessary concentration of the precursor amine (57 mM), which reacted with [ 18 F]fluorophenylazocarboxylic tert ‐butylester under basic conditions. The optimization of the base (Cs 2 CO 3 , 23 mM) and the adjustment of reaction temperature led to the radiochemical yield of 63% after 5 min at 35°C. The optimized reaction conditions were transferred on to the synthesis of [ 18 F]3 with an overall non‐decay corrected yield of 8‐12% in a specific activity of 32‐102 GBq/µmol after a total synthesis time of 30‐35 min. This provides a D 3 radioligand candidate with improved attributes concerning selectivity and radiosynthesis for further preclinical studies.